在细胞模型中,表观遗传调控蛋白 BRD4 的降解和抑制会加剧阿尔茨海默病相关的神经病理学。

Annals of the ICRP Pub Date : 2022-04-01 Epub Date: 2022-03-03 DOI:10.1016/j.jbc.2022.101794
Siyi Zhang, Ping Bai, Dan Lei, Yingxia Liang, Sherri Zhen, Grisilda Bakiasi, Hao Pang, Se Hoon Choi, Changning Wang, Rudolph E Tanzi, Can Zhang
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引用次数: 0

摘要

表观遗传调控在人类病理生理学中发挥着重要作用,这为通过靶向表观遗传途径干预人类疾病提供了机会。最近,临床前研究中新出现的证据表明,通过靶向表观遗传调控蛋白--含溴结构域蛋白 4(BRD4),开发阿尔茨海默病(AD)治疗药物具有潜力。然而,与阿尔茨海默病相关的病理事件亟需进一步的特征描述。在此,我们研究了药物降解或抑制 BRD4 对 AD 细胞模型的影响。有趣的是,我们发现 ARV-825 和 JQ1 对 BRD4 的降解和抑制作用都会显著增加淀粉样β(Aβ)的水平,而淀粉样β与 AD 的神经病理学相关。随后,我们研究了下调 BRD4 使 Aβ 水平升高的机制。我们发现,BRD4的降解和抑制都会增加BACE1的水平,而BACE1是负责裂解淀粉样β蛋白前体(APP)生成Aβ的酶。与 Aβ 的增加相一致,我们还发现,在三维-AD 人类神经细胞培养模型中,下调 BRD4 会增加与 AD 相关的磷酸化 Tau(pTau)蛋白。因此,我们的研究结果表明,下调BRD4并不是干预AD的可行策略。总之,我们的研究不仅表明 BRD4 是调节 BACE1 和 Aβ 水平的一种新型表观遗传学成分,而且还为针对 BRD4 的潜在临床应用提供了新颖的转化见解。
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Degradation and inhibition of epigenetic regulatory protein BRD4 exacerbate Alzheimer's disease-related neuropathology in cell models.

Epigenetic regulation plays substantial roles in human pathophysiology, which provides opportunities for intervention in human disorders through the targeting of epigenetic pathways. Recently, emerging evidence from preclinical studies suggested the potential in developing therapeutics of Alzheimer's disease (AD) by targeting bromodomain containing protein 4 (BRD4), an epigenetic regulatory protein. However, further characterization of AD-related pathological events is urgently required. Here, we investigated the effects of pharmacological degradation or inhibition of BRD4 on AD cell models. Interestingly, we found that both degradation and inhibition of BRD4 by ARV-825 and JQ1, respectively, robustly increased the levels of amyloid-beta (Aβ), which has been associated with the neuropathology of AD. Subsequently, we characterized the mechanisms by which downregulation of BRD4 increases Aβ levels. We found that both degradation and inhibition of BRD4 increased the levels of BACE1, the enzyme responsible for cleavage of the amyloid-beta protein precursor (APP) to generate Aβ. Consistent with Aβ increase, we also found that downregulation of BRD4 increased AD-related phosphorylated Tau (pTau) protein in our 3D-AD human neural cell culture model. Therefore, our results suggest that downregulation of BRD4 would not be a viable strategy for AD intervention. Collectively, our study not only shows that BRD4 is a novel epigenetic component that regulates BACE1 and Aβ levels, but also provides novel and translational insights into the targeting of BRD4 for potential clinical applications.

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来源期刊
Annals of the ICRP
Annals of the ICRP Medicine-Public Health, Environmental and Occupational Health
CiteScore
4.10
自引率
0.00%
发文量
3
期刊介绍: The International Commission on Radiological Protection was founded in 1928 to advance for the public benefit the science of radiological protection. The ICRP provides recommendations and guidance on protection against the risks associated with ionising radiation, from artificial sources as widely used in medicine, general industry and nuclear enterprises, and from naturally occurring sources. These reports and recommendations are published six times each year on behalf of the ICRP as the journal Annals of the ICRP. Each issue provides in-depth coverage of a specific subject area.
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